I-ACQUIRE Phase III Trial for Perinatal Arterial Stroke: Protocol Overview

1. Perinatal Arterial Stroke (PAS): A Phase III Multi-site Trial of I-ACQUIRE First Investigators Meeting Protocol Overview 1 May, 2019 Sharon Landesman Ramey, Ph.D. (Lead PI) Fralin Biomedical Research Institute (FBRI), Virginia Tech (Roanoke) Warren Lo, M.D. (Co-PI) Nationwide Children’s Hospital & The Ohio State University (OSU)

2. Perinatal Arterial Stroke (PAS): A Phase III Multi-site Trial of I-ACQUIRE • Sharon Landesman Ramey, Ph.D. (Lead PI) • Fralin Biomedical Research Institute (FBRI), Virginia Tech (Roanoke) • Warren Lo, M.D. (Co-PI) • Nationwide Children’s Hospital & The Ohio State University (OSU) • Stephanie DeLuca, Ph.D. & Craig Ramey, Ph.D. • Treatment Implementation Center Directors, FBRI, Virginia Tech (Roanoke) • Amy Darragh, Ph.D., OTR/L & Jill Heathcock, Ph.D., MPT • Central Assessment Center Directors, OSU • Max Wintermark, M.D. • Clinical MRI Center Director, Stanford University • Laura Bateman • National Study Coordinator, FBRI, Virginia Tech

3. The primary locations of the 12 I-ACQUIRE Sites Ann Arbor Atlanta Baltimore Boston Chicago Cincinnati Columbus Houston New Haven Philadelphia Roanoke San Diego

4. Stroke in Infants and Current Treatment Approaches • Pediatric arterial ischemic stroke occurs most frequently in infants • Incidence of Neonatal Arterial Ischemic Stroke (NAIS) is 1:2500 – 1:7700 live births • Incidence of presumed prenatal/perinatal stroke similar to NAIS (diagnosed at later ages after neuromotor impairment detected) COMBINED INCIDENCE = 1:1250 • No consensus rehabilitation for infants with post-stroke hemiplegia • Wide array of intervention approaches • Weekly low-dose OT and/or PT therapy is typical (not evidence-based) • Consensus from systematic reviews that constraint-induced movement therapy (CIMT) is the most efficacious treatment for children with hemiparesis • CIMT is considered high-intensity and actively shapes voluntary control • No adequately powered RCT of CIMT in infants/toddlers (< 24 mos) • No RCT of signature CIMT focused on infants/toddlers after stroke I-ACQUIRE IS A SIGNATURE FORM OF CIMT TESTED IN MULTIPLE RCTs

6. I-ACQUIRE Phase III Trial Specific Aims • Primary Aim: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to usual and customary treatment (U&CT) to increase upper extremity skills on the hemiparetic side at both end of treatment and 6 mos post-treatment • Secondary Aim: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to U&CT to improve use of the hemiparetic upper extremity in bimanual activities at both end of treatment and 6 mos post-treatment • Exploratory Aim: Explore the association between I-ACQUIRE treatment at Moderate and High Doses and gains in gross motor, language, and cognition outcomes (i.e., cross-domain or “spillover” effects of treatment)

7. Public Health Impact of I-ACQUIRE Phase III Trial • Estimated 3400+ new cases/yr of Perinatal Arterial Stroke (PAS) in U.S. • High likelihood of lifelong motor and cognitive impairments, especially hemiparesis • Immense cost burden for families, the healthcare and education systems, and society If I-ACQUIRE (at one or both doses) proves efficacious, then the field will have the critically needed Phase III confirmatory evidence to transform evidence-based rehabilitation and improve clinical outcomes for infants and toddlers with PAS.

8. Eligibility Screening and Enrollment (N=240) Perinatal Arterial Stroke (PAS) diagnosis with confirmatory MRI & hemiparesis (8–24 mos) DESIGN FOR PHASE III I-ACQUIRE TRIAL Random Assignment (centralized) to I-ACQUIRE DOSAGE GROUPS or U&CT Usual & Customary Tx (U&CT) (N=80) documented Moderate Dose I-ACQUIRE (N=80) 3 hr/day x 20 High Dose I-ACQUIRE (N=80) 6 hr/day x 20 Baseline (pre-treatment) Assessment Battery Blinded Assessments (videorecorded) & Parent Ratings Implementation of Treatment Protocol (4 weeks) Active Central Monitoring, Weekly Videorecording, & Therapy Logs Post-treatment Assessment Batteries: Immediate & 6 mos. Blinded Assessments (videorecorded) & Parent Ratings U&CT Parents offered choice of I-ACQUIRE Dosage (Crossover)

9. Inclusion/Exclusion Criteria forI-ACQUIRE Phase III Trial • Inclusion criteria • 8-24 mos old at time when treatment delivered • Perinatal Arterial Ischemic Stroke (PAS) diagnosed • PAS confirmed with clinical MRI(high-quality, standardized) • Hemiparesis • Parents able to participate in home-based intervention • present at least 1 day/wk for therapy and 45 min/day practice at home • Exclusion Criteria • Fragile medical health • Prior receipt of CIMT ≥ 2 hrs/day x 10 days • Botox within past 3 mos • In prior studies of ACQUIRE, parent willingness to enroll is high (93-95%) and attrition rate is low (5-7%). Option of crossover (delayed) treatment is important.

10. 8 Core Treatment Components (bold font represents core features of all signature forms of CIMT) • Constraint of the less-impaired upper extremityfor first 17 days of 20 treatment days. The lightweight cast is worn continuously. • High (intensive) dosage of treatment – either 3 or 6 hrs/day, 5 days/wk for 4 weeks – provided by protocol-trained OTs or PTs (licensed, certified) • Operant conditioning techniques to shape and improve skills and abilities, combined with practice variation; emphasis on play, self-help, fun, and use of a variety of individualized reinforcers • Therapy in natural settings (e.g., home, child care center) • Shaping includes total body/trunk and bimanual activities (as well as traditional arm/hand therapy activities) • Parent-Therapist Partnership(formal module) all 4 weeks • Daily therapy sessions documented • Transfer Packageto promote future skill and motor development

11. Save these 2019 dates: Upcoming I-ACQUIRE events • Thursday, 18 April 2019 from 2:00 – 3:00 p.m.: Webinar about the Clinical Trial Agreement (CTA) and Payment Schedule (U of Cincinnati) • Thursday, 25 April 2019 from 2:00 – 3:00 p.m.: Webinar about the Central Institutional review Board (CIRB) Process and Local Site Compliance (U of Cincinnati) • Tuesday, 30 April 2019 in Chicago/Hilton Chicago O-Hare Airport (7:00 – 8:30 p.m.): Evening reception for I-ACQUIRE Study team and local site PIs, Co-Is, and Study Coordinators • Wednesday, 1 May 2019 in Chicago/Chicago O-Hare Airport (8:30 a.m. – 4:00 p.m.): First Meeting of Local Sites and I-ACQUIRE national team • Sunday, 16 June 2019 – Monday, 17 June 2019: First meeting of Parent Council in Roanoke • Monday, 17 June 2019 (evening orientation) in Roanoke – Friday, 21 June: Required training for I-ACQUIRE therapists • Mid-June to mid-July 2019: Required training (webinars and calls) for assessors • 1 August 2019: Open to consent, randomize, schedule, and implement assessments and treatments

12. Some unique aspects of I-ACQUIRE in StrokeNet • First pediatric trial in StrokeNet • First trial to engage patient advocates (parents) in the trial through a Parent Council • Designed to set the stage for Implementation Research. Important because I-ACQUIRE protocol is complex, intensive, and requires training to ensure high fidelity – thus challenging traditional clinical treatment of this patient population. • Well-suited to advancing knowledge about differential responses to treatment and theories re: neuroplasticity in young children after stroke, including potential biomarkers for individualizing treatment choices. • Explicit shared goal to begin to create an even stronger multidisciplinary network of pediatric neurology and rehabilitation scientists – to exchange ideas and propose other studies in the near future.

13. Stephanie C. DeLuca, PhD NEUROMOTOR RESEARCH CLINIC

14. The EIGHT I-ACQUIRE Treatment Components

15. Video of Weekly Progress of Infant over 4 week treatment

18. Differences with Infants I-ACQUIRE ACQUIRE 1. Constraint of the less or unimpaired upper extremity 2. High dosage (likely minimum threshold: 2-hr sessions per day for 5 days/wk) 3. Use of shaping techniques and repetitive practice with task variation 4. Learning functional skills in natural and diverse settings 5. Transition (post-therapy) planning for maintenance of gains 1. Constraint of the infant’s less-impaired upper extremity. 2. High dosage of treatment – either 3 or 6 hrs/day, 5 days/wk for 4 weeks. 3. Operant conditioning techniques to shape and improve upper extremity (UE) skills;. 4. Provision of therapy in natural settings. 5. Emphasis on total body and bimanual activities 6. Home Treatment Module developed as an active Parent-Therapist Partnership. 7. Documentation of daily therapy sessions. 8. Transfer Package to promote future progress.

19. MR 3 Cycle Operant Conditioning Operant conditioning (or instrumental learning) refers to learning promoted by specific behavioral techniques. Designed to promote and maintain learning, through response-contingent feedback.

21. Video of parent training and showing technique of I-ACQUIRE

22. What makes I-ACQUIRE Different from Traditional (PT/OT) Therapy? Traditional Therapy I-ACQUIRE Focus on Learning Principles Progression expected both within each session and across sessions Small Incremental Steps (as dictated by learning principles) Specificity of Prompts & Reinforcements Success oriented Intensity There is Greater Number of Repetitions Affords Greater Opportunity for Refinement, Solidification (skill and neural representation), & Generalization • Less operationalized definitions of learning principles • Good Therapists do much of the same learning principle techniques in their treatment sessions • Less opportunity to see progression • Success becomes harder for both the child and the therapist across time

23. Assessment Core Jill Heathcock PT, PhD – Associate Professor Amy Darragh OTR/L, PhD – Associate Professor Thais Cabral OT, PhD – Post Doctoral Fellow The Ohio State University

24. Outcome measure • Emerging Behaviors Scale • Bayley Scales of Infant Development (Bayley-III) • Gross Motor Function Measure-66 (GMFM-66) • Mini Assisting Hand Assessment (mini-AHA) • Time points • Pre-treatment, Post treatment 1 month, Post-treatment 6 months

25. Blinded Assessors • Complete the outcome measures • Emerging Behaviors Scale – partial, confirmed centrally • Bayley Scales of Infant Development (Bayley-III) – full, with modifications for R + L on FM subscale • Gross Motor Function Measure-66 (GMFM-66) – full • Mini Assisting Hand Assessment (mini-AHA) – administer the play session, scored centrally. • All sessions are videotaped and transfer to the OSU • IACQUIRE computer, tripod

26. Blinded Assessors • PT, OT, developmental psychology, psychologists, person with experience conducting evaluation with children • Preferably with age range or some assessment • *not the treating therapist or study coordinator* (maintain blinding is the goal) • Each site = 2 blinded assessors • Attend training, achieve and maintain >85% reliability on tools • Prior Study (June) • Web-based training with Assessment Core (July) • Score videos for reliability • Send back to assessment core a child/assessor interaction + score • Administration and score (hemiparesis preferred) • Yearly reliability checks to avoid and correct drift

27. Parent Outcome Measures

28. Parent Measures Parent Report Infant Motor Activity Log MacArthur Bates Communicative Development Inventories (CDI-III)

29. I-MAL Evaluates the infant’s frequency and quality of affected UE movement in everyday tasks. Collected at Pre, Post, 6 mos Parent rates how often (never-always) & how well (poor-normal) child uses affected-UE for 20 infant arm/hand tasks. Sample items: Hold a bottle/cup, Eat finger foods, Pick up a cylindrical object (e.g., crayon, marker, bottle, cup, or rattle).

30. MacArthur Bates Communicative Development Inventories (CDI-III) Assesses early language skills in infants & toddlers: (Comprehension, Vocabulary, Grammatical Skills, Nonverbal Gestures and Actions ) Collected at Pre, Post, 6-mos Available for Infants and Toddlers 8 – 30 months Forms can be completed in 20 – 45 minutes Parents can complete at home

31. Parent Measures Parent Experiences and Background Demographics Perceived Stress Scale plus stress schedule Pre-treatment and Post-treatment Questionnaire Report of Therapy Experiences Report of Parent-Therapist Information Exchange Physician Administered Neurological Exam: Medical History and PSOM (pre-only)

32. Perceived Stress Assesses perceptions of stress; specifically, the extent to which situations are perceived as stressful Parent’s self-reported perceptions of stress are assessed at baseline, post-treatment 1-month, and at post-treatment 6-month. Includes Perceived Stress Scale and Self-reported perceptions of stress Parents can complete at home

33. Pre and Post-Questionnaire General information about therapy and therapist

34. Parent Measures Report of Therapy Experiences Information about the therapies that the children in the study have participated in

35. Parent Measures Physician Administered Neurological Exam: Medical History and PSOM

36. Parent – Therapist Information Exchange Assesses process of goal setting; preparation and training; role of parent in therapy Completed by both parent and therapist post-treatment